CHEMSUSCHEM MINIREVIEWS DOI: 10.1002/cssc.201402874

Diazo Compounds in Continuous-Flow Technology Simon T. R. Mller and Thomas Wirth*[a] Diazo compounds are very versatile reagents in organic chemistry and meet the challenge of selective assembly of structurally complex molecules. Their leaving group is dinitrogen; therefore, they are very clean and atom-efficient reagents. However, diazo compounds are potentially explosive and extremely difficult to handle on an industrial scale. In this review, it is discussed how continuous flow technology can help to

make these powerful reagents accessible on large scale. Microstructured devices can improve heat transfer greatly and help with the handling of dangerous reagents safely. The in situ formation and subsequent consumption of diazo compounds are discussed along with advances in handling diazomethane and ethyl diazoacetate. The potential large-scale applications of a given methodology is emphasized.

1. Introduction 1.1. General introduction Modern synthetic chemistry faces the challenge of providing society with valuable products, such as pharmaceuticals, materials, and fertilizers, while being environmentally benign and safe. For this purpose, reagents are required that are able to assemble structurally complex molecules in an atom-economic fashion with high chemo-, regio-, and stereoselectivity. Of the broad range of reagents and functional groups available to meet this task, diazo compounds stand out with their unique ability to functionalize nonactivated bonds. Consequently, their chemistry has been extensively studied on the laboratory scale, in particular, in C H insertion reactions,[1] X H insertion reactions,[2] cyclopropanations,[3] ylide formation,[4] multicomponent reactions,[5] and ring expansions.[6] Although diazo compounds are sustainable reagents in their ability to reduce the number of synthetic steps and waste generated, they cannot be considered as being safe or easy to handle. Diazo compounds are highly energetic compounds, some of them are even explosives.[7] Furthermore, through decomposition, diazo compounds release one equivalent of nitrogen; this leads to a significant buildup of pressure under largescale batch conditions. Therefore, the industrial, large-scale use of diazo compounds is rare. Less efficient but safer synthetic routes are usually employed instead; this often leads to larger amounts of waste being produced and increased energy consumption. Hence, a platform for the safe handling of diazo compounds would be desirable.

1.2. Continuous-flow technology Continuous-flow chemistry has emerged within the last 15 years as a valid competitor to classical batch and semibatch [a] S. T. R. Mller, Prof. Dr. T. Wirth School of Chemistry, Cardiff University Park Place, Cardiff CF10 3AT (UK) E-mail: [email protected]

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synthesis.[8] In particular, with respect to the 12 principles of green chemistry,[9] continuous-flow technology can play a major role in improving chemical processes.[10] One of the most important benefits arises from the inherent safety of reactions performed in microreactors. This inherent safety derives from the high surface-to-volume ratio of microstructured devices. Leading to a much better heat exchange, adiabatic conditions provoking a thermal runaway are not attained.[11] Moreover, the cooling capacity is often much higher; therefore, reducing the amount of energy required to keep a system cooled and safe. In addition, the quantity of materials with dangerous properties present at any time in the device is significantly lower for continuous flow than that for batch. As seen in Table 1, all of these characteristics dramatically favor microstructured and tubular systems over classical stirred tanks for handling energetic compounds.

Table 1. Physical parameters of different reactor types.[12] Reactor[a]

Mass of contents

U[b] [W m 2 K 1]

Cooling capacity [W kg 1 K 1]

stirred tank[a] tubular[a] micro[b]

10 000 kg 78.5 g 78.5 mg

500 1000 20 000

1 400 800

[a] Reactor dimensions: stirred tank: 10 m3 ; tubular: 78 mL, d = 1 cm, l = 1 m; micro: 78 mL, d = 0.1 mm, l = 1 m. [b] Heat transfer.

Consequently, continuous-flow chemistry has found several applications in handling dangerous, toxic, and corrosive reagents.[13] As part of this process, diazo compounds have been investigated in continuous flow, with the goal of unlocking the great potential of these powerful reagents for industrial organic synthesis.

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2. Diazo Compounds in Flow

IR system to monitor the concentration of diazomethane present in the nitrogen gas flow. In subsequent studies by Lçbbecke et al.[15] and later by 2.1. Diazomethane Stark et al.,[16] the production of diazomethane was performed in microstructured devices coupled to methylation of benzoic The use of diazo compounds in continuous flow emerged as acid. Stark et al. investigated solvent choices to prevent clogone of the first fields of study for organic synthesis in microging, and this led to an inherently safe setup with a turnover reactors. In the beginning, this was mainly driven by the desire of 2.5 mol per day of diazomethane. However, because Diazald to develop safe industrial-scale operations for diazomethane. requires the use of a basic solution of potassium hydroxide to In a key publication, Proctor and Warr from Phoenix Chemicals form diazomethane, base-sensitive compounds, such as anhydescribed the use of diazomethane for the formation of adrides, are not accessible through this method. chloroketone 3 (Scheme 1).[14] Their process was based on the A powerful solution to this problem was later provided by Kim and co-workers.[17] In a dual-channel microreactor, a highly hydrophobic poly(dimethylsiloxane) (PDMS) membrane allowed the separation of diazomethane from the aqueous solution of Diazald in which it was generated (Figure 1). Unfortunately, due to the small volume (60 mL) of the device, the Scheme 1. In situ produced diazomethane for the formation of a-chloroketone 3. daily output of this approach was limited to less than CBz = carbobenzyloxy. 3 mmol. Furthermore, some nonpolar organic solvents, such as THF, cannot be used with the PDMS formation of diazomethane in a continuous fashion from Diamembrane because they would lead to swelling of the memzald in a solvent mixture of DMSO/H2O. Diazomethane formed brane. was carried into a solution containing 1 by using a flow of nitrogen gas. In addition to extensive risk assessments in course of their studies on diazomethane, they also installed an in-line

Simon T. R. Mller was born 1986 in Saint-Denis, France. He obtained his B.Sc. from the University of Osnabrck, Germany (chemistry major, French minor), and his M.Sc. in biological chemistry from the University of Vienna, Austria (with distinction). He had research stays in Grenoble, France; Ghent, Belgium; and at Pierre Fabre in Gaillac, France. Since October 2012, Simon has been a PhD student in organic chemistry at Cardiff University working on diazo compounds in continuous-flow technology. Thomas Wirth has been Professor of Organic Chemistry at Cardiff University since 2000. He has been invited to a number of places in Canada and Japan as a Visiting Professor. In 2000, he was awarded the Werner Prize from the New Swiss Chemical Society and received a JSPS Furusato Award in 2013. His main research interests concern stereoselective electrophilic reactions; oxidative transformations with hypervalent iodine reagents, including mechanistic investigations; and organic syntheses performed in microreactors.

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Figure 1. PDMS membrane for diazomethane extraction.

Kappe et al.[18] developed a similar approach by using the tube-in-tube reactor AF-2400 introduced by Ley et al. in 2010 (Figure 2).[19] With this setup, it was possible to increase the daily output to up to 35 mmol. They coupled the generation of diazomethane with methylation reactions, cyclopropanations, and cycloaddition reactions and studied the use of their method for the synthesis of antiretroviral drugs.

Figure 2. AF-2400 tube-in-tube reactor (the blue tube is gas permeable) for the formation and use of diazomethane. R1 = Ph; R2 = COMe.

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CHEMSUSCHEM MINIREVIEWS A large-scale approach was reported by Rossi et al. that allowed the production of up to 19 mol per day of diazomethane.[20] Diazomethane was generated by base-induced decomposition of N-methyl-N-nitrosourea. The Corning advanced-flow reactor GEN1 was used to process the required quantities of diazomethane and the subsequent methylation of benzoic acid. Yields were almost quantitative; thus, providing a very efficient way to make large quantities of esters. Ley and co-workers studied the safer and more expensive diazomethane replacement trimethylsilyl diazomethane in an acylation reaction to make terminal diazo ketones.[21] These reagents were subsequently used for the formation of quinoxalines in a cycloaddition reaction. Originally, Ley et al. were investigating the formation of diazomethane by pumping potassium tert-butoxide through cartridge-based, polymer-supported Diazald. Unfortunately, this strategy was unsuccessful because of low yields and inconvenient pressure buildup in the cartridges. An application of the use of diazomethane in the synthesis of the pharmaceutically relevant intermediate (S)-1-benzyl-3diazo-2-oxopropylcarbamic acid tert-butyl ester was shown by Liotta et al.[22] Trimethylsilyl diazomethane was used for a homologation reaction with a mixed anhydride derived from NBoc-(S)-phenylalanine (Boc = tert-butyloxycarbonyl) in a continuous-flow microreactor. 2.2. Ethyl diazoacetate After the development of several powerful protocols for the preparation and use of diazomethane, focus shifted to ethyl diazoacetate. Ethyl diazoacetate is considered to be one of the most powerful diazo-based reagents in synthesis and is considerably easier to handle than diazomethane. However, it is still potentially explosive and toxic. Early studies by Martnez-Merino et al.[23] reported asymmetric catalytic cyclopropanation reactions of styrene derivatives with ethyl diazoacetate by using heterogeneous catalysis in flow chemistry. Supercritical carbon dioxide could be employed as a solvent to make the process benign. Interestingly, the use of solid-support catalysis increased the potency of copper–pyridineoxazoline for asymmetric induction up to sevenfold compared with homogeneously catalytic systems. Recently, Caselli and co-workers used carbon dioxide as a carrier to perform cyclopropanations with ethyl diazoacetate under copper catalysis with pyridine-containing tetraazamacrocyclic ligands to give moderate to good diastereo- and enantioselectivities.[24] Hayes and co-workers used ethyl diazoacetate in a Roskamp reaction with aldehydes catalyzed by boron trifluoride etherate (Figure 3).[25] The resulting b-ketoester was used directly without purification in a condensation reaction with 1,2-diaminobenzene to form pyrimidines in batch. This provided a powerful approach by using two dangerous reagents in a one-flow setup to obtain valuable heterocyclic building blocks. These two reagents were also used in a ring-expansion reaction published by Zhang et al. from Johnson & Johnson.[26] The continuous-flow system for the ring-expansion of N-Boc-4-piperidone  2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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Figure 3. Use of ethyl diazoacetate to make b-ketoesters in flow. BPR = Back pressure regulator, DBU = 1,5-diazabicyclo[5.4.0]undec-5-ene. R1 = aryl, alkyl; R2 = aryl, alkyl, SH, H.

makes this highly exothermic reaction (Tad = 45.63 8C) safe, rapid (1.8 min residence time), and selective (89 % yield). For industrial purposes, however, it would be highly desirable to find a technique that forms and consumes ethyl diazoacetate in situ in a microreactor setup. The formation of ethyl diazoacetate from glycine ethyl ester with sodium nitrite in acidic medium was recently studied in detail by Rutjes et al.[27] Optimization studies were performed by using design of experiment (DoE) algorithms and effects of temperature, residence time, and amounts of sodium nitrite were studied. Excellent yields were obtained with 1.5 equivalents of NaNO2 at 50 8C in a 20 s reaction time. Up to 175 mmol of ethyl diazoacetate can be made per day with this protocol. Shortly after these investigations, the groups of Kim[28] and Wirth[29] independently published continuous-flow methods to form and react ethyl diazoacetate in one setup. In the experiments by Kim et al., ethyl diazoacetate formed in a biphasic solvent mixture (toluene/water) from which it was extracted instantly. The organic feed could then be reacted either in an aldol-type addition on aldehydes or in a Roskamp reaction with BF3·EtO2 (Figure 4) In our work, ethyl diazoacetate was formed in the first reactor in water and subsequently added to aldehydes in DMSO to provide a-diazo-b-hydroxyesters in high yields with short residence times and high concentrations; this makes it an appealing process for industrial applications. This two-step process can be applied to a rhodium acetate catalyzed 1,2-hydride shift to provide b-ketoesters in a three-step flow process (Figure 5). Immense interest from industry in processes involving diazo compounds in continuous-flow systems is nicely demonstrated by Poechlauer and co-workers from DSM.[30] They synthesized and applied diazomethane and ethyl diazoacetate in continuous-flow systems for plant-sized processes.

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2.3. Miscellaneous The chemistry of diazo compounds is not limited to diazomethane and ethyl diazoacetate. Several powerful protocols have been developed to use diazo compounds in inter- and intramolecular reactions in continuous flow. Again, the explosive nature of the diazo functionality makes continuous flow appealing for larger scale applications. Hayes and co-workers studied Bamford–Stevenstype reactions with hydrazones for N H and O H insertions,[31] as well as for S H and P H insertions.[32] Figure 4. Multiple reaction and liquid/liquid phase separation in the use of ethyl diazoacetate (EDA). Reproduced from Ref. [28] with permission from The Royal Society of Diazo esters are formed in situ by using triethylamine Chemistry. as a base for the decomposition of tosyl hydrazones. The reaction mixture went through a scavenger column to trap the sulfinic acid byproduct and the stream of diazo ester was added in a semibatch manner to solutions containing alcohols, amines, sulfides, sulfinates,[33] and H-phosphonates under rhodium or copper catalysis (Figure 6). A similar approach to generate diazo compounds from tosyl hydrazones was used by Kupracz and Kirschning to form biarylmethanes.[34] Based on the discovery by Barluenga et al. of the metal-free, base-induced coupling of aryl tosyl hydrazones with aryl boronic acids,[35] Kirschning developed a two-step continuous-flow protocol. In the first reactor, ketones and tosyl hydrazone reacted together on steel beads heated to 80 8C. The boronic acid was added subsequently and reacted on steel beads with potassium carbonate as a heterogeneous catalyst at 120 8C to give biarylmethanes in good yields. Another heterogeneous catalysis approach to the chemistry Figure 5. Multiple-step flow setup to form and consume ethyl diazoacetate of diazo compounds in continuous flow was used by the in flow. R = aryl, alkyl. group of Hashimoto for the use of chiral dirhodium(II) catalysts in asymmetric cycloaddition reactions (Figure 7).[36] In the case of dirhodium(II) catalysis, the use of recyclable solid-support systems is very appealing due to the high costs of rhodium. Excellent enantioselectivities could be achieved with catalyst loadings as low as 0.0067 mol %. Sand is used as a packing material because it does not swell in trifluorotoluene, which is the solvent used in this cycloaddition. A very interesting partnership is arising between the fields of photochemistry and continuous-flow technology.[37] In accordance with the Beer–Lambert law, the efficiency of the absorbance of photons inside a medium decreases exponentially with the path length a photon has to cross. This makes the scaling up of photochemical reactions in batch ex- Figure 6. S H and P H insertion after the formation of diazoesters from tosyl hydra1 2 tremely difficult and leads to inefficient processes zones. R = aryl, alkyl; R = alkyl. with the formation of many byproducts. Continuousflow chemistry overcomes these problems due to the miniaturized structures used and the ease of scale up. Konomode, the rearrangement was much quicker in continuous pelski et al. performed a photoinduced Wolff rearrangement of flow and provided easier scale up. diazo compounds to obtain synthetically valuable trans-b-lacRecently, Danheiser and co-workers from the Massachusetts tams (Figure 8).[38] They compared batch and flow processes in Institute of Technology studied the benzannulation reactions of ynamides with diazo ketones.[39] The pericyclic cascade terms of the yield, selectivity, and efficiency. Although the yields dropped slightly compared with those obtained in batch mechanism involved a Wolff rearrangement, [2+2] cycloaddi 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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Figure 7. Solid-support asymmetric catalysis for cycloaddition reactions in flow by using a chiral rhodium(II) catalyst.

Figure 8. A comparison of flow and batch photochemistry for the Wolff rearrangement to give b-lactams. LiHMDS = lithium hexamethyldisilazide, Bn = benzyl, Tr = trityl, CFL = compact fluorescent light, MVL = mercury vapor lamp.

tion, four-electron electrocyclic cleavage of the cyclobutenone moiety, and six-electron electrocyclic ring closure. The continuous-flow method gave comparable yields to those obtained with the batch process, while reducing the reaction time from 3–8 h to 21 min. Benzannulation can subsequently be coupled to ring-closing metathesis in a batch process to provide highly substituted polycyclic aromatic systems, as illustrated in Scheme 2.

3. Summary and Outlook Early research in the area of diazo compounds in continuousflow technology focused on protocols for handling diazomethane. Other reactions performed with diazo compounds in  2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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Scheme 2. Benzannulation reactions of ynamides with diazo ketones. Z = CO2Me, PO(OEt)2, SO2Ar; R1, R2 = alkyl, aryl; R3 = H, alkyl; R4 = Me, Bn; R5 = hexyl.

flow were typically one-step reactions that had been known in batch before. However, recently methods have been developed to shorten several steps from formation to modification and consumption of the highly energetic diazo moiety. These multistep processes can provide safe products from safe starting materials without any need to ever handle large amounts of diazo compounds at any given time. Thus, in recent years, liquid/liquid phase separators,[40] solvent evaporation systems,[41] and total synthesis protocols have been developed for flow chemistry.[42] The benefits arising from using continuous flow as a platform for handling diazo compounds explain increasing interest from research groups in academia and industry in this field. However, there are still several challenges to overcome and opportunities to take. So far, most reactions investigated in flow were known in batch systems. Flow chemistry has improved output and selectivity, but could it also lead to completely new reactions? A more detailed look into tuning of selectivities would be valuable. The groups of Yoshida and Ley found that lithiation reactions provided very different products in microstructured systems.[43] Considering how challenging the tuning of selectivities can be in carbene chemistry (e.g., in multicomponent reactions), microreactor technology could help. Nonstabilized diazo compounds, such as phenyl diazomethane and diphenyl diazomethane, have received little attention in recent years in batch chemistry. Flow chemistry could help to uncover more of the reactivity of nonstabilized diazo compounds. Another tool in continuous-flow chemistry that can have a major impact on synthetic chemistry is online monitoring of reactor progress.[44] In the case of diazo compounds, this would provide access to yields of a diazo group formation step without requiring the isolation of the reactive intermediate. Furthermore, online techniques can give important information about side-product formation and kinetics. ChemSusChem 0000, 00, 1 – 7

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CHEMSUSCHEM MINIREVIEWS In conclusion, microreactor-based continuous-flow technology is an excellent fit to the challenges chemists are facing when working with diazo compounds. The potential of diazo compounds to be atom-economic, selective, and green reagents (nitrogen is a very clean leaving group) for process chemistry could be finally unlocked. It will be exciting to see further developments of diazo compounds in continuous flow in the coming years.

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[20] [21] [22]

[23]

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Received: August 21, 2014 Published online on && &&, 0000

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MINIREVIEWS S. T. R. Mller, T. Wirth* && – && Diazo Compounds in Continuous-Flow Technology

Not off like a bomb! Diazo compounds are highly versatile building blocks in synthesis for the selective assembly of structurally complex molecules. Their safe in situ formation and subsequent

handling in microstructured devices is discussed along with advances on handling diazomethane and ethyl diazoacetate.

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Diazo compounds in continuous-flow technology.

Diazo compounds are very versatile reagents in organic chemistry and meet the challenge of selective assembly of structurally complex molecules. Their...
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